The overarching goal of this proposal is to establish an Autoimmunity Center of Excellence at the University of Rochester. This goal is based upon our belief that the understanding of human autoimmunity requires the concerted effort of basic and clinical scientists working together in an intellectual framework that provides constant feedback between bench studies and therapeutic interventions. Our Center will concentrate on studies relevant to the pathogenesis and treatment of Type 1 Diabetes Mellitus (T1DM), Multiple Sclerosis (MS) and Systemic Lupus Erythematosus (SLE). Both types of studies are based on the unifying idea that abnormalities of B- and T-cell function are at the core of these autoimmune diseases. Basic Project 1 will investigate the role of regulatory T-cells (Treg) in the pathogenesis of T1DM and will generate new reagents that will allow investigators to more specifically identify human Treg cells. Basic Project 2 will elucidate the role of IL- 12p40 monokines in MS and determine whether defects in Treg function exist in patients with this disease. Basic Project 3 will study B-cell homeostasis and the cellular origin of disease-specific autoantibodies in SLE. In addition, this project will investigate whether abnormal Treg function contributes to the activation of autoimmune B-cells and T-cells in SLE. These pathogenic mechanisms will serve as the theoretical basis for our clinical trials. Clinical Project 1 will study the clinical and immunological consequences of B-cell depletion in SLE using the anti-CD20 monoclonal antibody Rituximab. Clinical Project 2 will test the clinical and immunological effects of anti-IL-12 in patients with MS. We expect that the studies proposed will result in information that will not only improve our understanding of the disease in question but will also suggest new avenues of research for the other autoimmune diseases targeted by our Center.